Carvedilol sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARVEDILOL SANDOZ®

Composition:

Active substance: carvedilol;

One tablet contains 12.5 mg or 25 mg of carvedilol;

Excipients:

Tablets of 12.5 mg: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone K30, colloidal anhydrous silicon dioxide, magnesium stearate, iron oxide red (E 172), iron oxide yellow (E 172);

Tablets of 25 mg: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone K30, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Carvedilol Sandoz®, 12.5 mg tablets: dark pink, round, convex tablets with a score line; engraved with С3 on one side.

Carvedilol Sandoz®, 25 mg tablets: round, convex tablets of white or almost white color, with a score line; engraved with С4 on one side.

Pharmacotherapeutic group. α- and β-adrenoreceptor blockers.

ATC code C07AG02.

Pharmacological Properties

Pharmacodynamics

Carvedilol is a non-selective adrenergic receptor blocker with multiple effects. It blocks α1-, β1-, and β2-adrenergic receptors. Carvedilol exerts organ-protective effects and acts as a potent antioxidant by scavenging reactive oxygen species (free radical scavenging activity). Carvedilol is a racemic mixture; both enantiomers, R-(+) and S-(-), exhibit similar α-blocking and antioxidant properties. Carvedilol has anti-proliferative effects on vascular smooth muscle cells. Clinical studies measuring various markers during long-term carvedilol therapy have demonstrated reduced oxidative stress in patients.

The beta-blocking effect is non-selective for β1- and β2-adrenergic receptors and is attributed to the S-(-) enantiomer.

Carvedilol has no intrinsic sympathomimetic activity. Like propranolol, it possesses membrane-stabilizing properties. Carvedilol suppresses the renin-angiotensin-aldosterone system via beta-blockade, reducing renin release, thereby minimizing fluid retention.

Carvedilol reduces peripheral vascular resistance through blockade of α1-adrenergic receptors. It attenuates the increase in arterial blood pressure induced by phenylephrine, an α1-adrenergic agonist, but does not affect the pressor response to angiotensin II.

Carvedilol has no adverse effect on lipid profile. The normal high-density lipoprotein to low-density lipoprotein (HDL/LDL) ratio remains unchanged.

Clinical Efficacy

Arterial Hypertension

Carvedilol reduces arterial blood pressure in patients with arterial hypertension due to combined β-blockade and α1-mediated vasodilation. The reduction in blood pressure is not associated with a compensatory increase in total peripheral resistance, which is commonly observed with pure beta-blockers. Heart rate is slightly reduced. Renal perfusion and kidney function are preserved. During carvedilol therapy, cardiac stroke volume is maintained while total peripheral resistance decreases. Carvedilol does not impair blood flow to specific organs and vascular beds such as kidneys, skeletal muscles, forearms, legs, skin, brain, or carotid arteries. Cold extremities and early fatigue during physical exertion are rarely observed. The sustained antihypertensive effect of carvedilol has been demonstrated in several controlled, double-blind studies.

Ischemic Heart Disease

In patients with ischemic heart disease, carvedilol exhibits anti-ischemic (increased total exercise time, time to 1 mm ST-segment depression, and time to onset of angina) and anti-anginal properties, which are maintained during long-term therapy. Acute hemodynamic studies have shown that carvedilol significantly reduces myocardial oxygen demand and sympathetic nervous system activity. Additionally, it reduces preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and afterload (total peripheral resistance).

Subjective Parameters

Carvedilol did not affect health-related quality of life (a primary endpoint in one trial), as measured by a standardized questionnaire. However, in most trials, a significant improvement in overall well-being was observed, as assessed by both patients and investigators.

Renal Function Impairment

A meta-analysis of large-scale, placebo-controlled clinical trials involving more than 4,000 patients with mild to moderate chronic renal impairment indicated that carvedilol treatment provides benefit in patients with left ventricular dysfunction, with or without symptomatic heart failure, by reducing overall mortality and the incidence of heart failure events.

Pharmacokinetics

Absorption

After oral administration of 25 mg capsules in healthy volunteers, carvedilol is rapidly absorbed, with peak plasma concentration (Cmax) of 21 mg/L reached at approximately 1.5 hours (Tmax). A linear relationship exists between Cmax values and dose.

Following oral administration, carvedilol undergoes extensive first-pass metabolism, resulting in an absolute bioavailability of approximately 25% in healthy volunteers. Carvedilol is a racemic mixture, and S-(-)-enantiomers appear to be metabolized more rapidly than R-(+)-enantiomers, resulting in an absolute oral bioavailability of 15% for S-carvedilol compared to 31% for R-carvedilol. Peak plasma concentration of R-carvedilol is approximately twice that of S-carvedilol.

In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in carvedilol availability has also been confirmed in vivo in healthy volunteers.

Distribution

Carvedilol Sandoz® is highly lipophilic, with approximately 95% plasma protein binding. Its volume of distribution (VDss) ranges from 1.5 to 2 L/kg.

Biological Transformation

In all studied animal species and in humans, Carvedilol Sandoz® is almost completely metabolized in the liver via oxidation and conjugation into several metabolites. Demethylation and hydroxylation on the phenolic ring yield three active metabolites with beta-blocking activity. In animals, the 4’-hydroxyphenol metabolite exhibits 13 times greater beta-blocking activity than carvedilol. Compared to carvedilol, these three active metabolites show only weak vasodilatory effects. Peak concentrations (Cmax) of active metabolites are reached within 1 hour: M2 3.9 ng/mL, M4 4.1 ng/mL, M5 3.3 ng/mL (approximately 20% of the carvedilol Cmax of 49 ng/mL).

Additionally, two hydroxycarbazole metabolites are very potent antioxidants, with activities 30–80 times stronger than that of carvedilol.

Pharmacokinetic studies in humans have shown that the oxidative metabolism of carvedilol is stereoselective. In vitro studies indicate that various cytochrome P450 isoenzymes, including CYP2D6, CYP3A4, CYP2E1, CYP2C9, and CYP1A2, may be involved in oxidation and hydroxylation processes.

Studies in healthy volunteers and patients have shown that R-enantiomers are metabolized predominantly by CYP2D6, while S-enantiomers are metabolized mainly by CYP2D6 and CYP2C9.

Genetic Polymorphism

Clinical pharmacokinetic studies in humans have demonstrated that CYP2D6 plays an important role in the metabolism of both R- and S-carvedilol. Thus, plasma concentrations of R- and S-carvedilol are increased in CYP2D6 poor metabolizers. The influence of CYP2D6 genotype on the pharmacokinetics of R- and S-carvedilol has also been supported by population pharmacokinetic studies, although other studies have not confirmed this observation. This suggests that CYP2D6 genetic polymorphism may have limited clinical significance.

Elimination

After oral administration, the elimination half-life of Carvedilol Sandoz® is approximately 6–10 hours. After a single 50 mg dose, nearly 60% of the dose is excreted via bile as metabolites and eliminated in feces over 11 days. Following single oral administration, only about 16% is excreted in urine as unchanged carvedilol. Less than 2% of the unchanged drug is excreted in urine. After intravenous infusion of 12.5 mg in healthy volunteers, plasma clearance of carvedilol is approximately 600 mL/min, with an elimination half-life of nearly 2.5 hours. In all subjects, the half-life of the 50 mg capsule was approximately 6.5 hours, consistent with the actual absorption half-life of the capsule. After oral administration, total clearance of S-carvedilol is approximately twice that of R-carvedilol.

Pharmacokinetics in Special Populations

Patients with Renal Impairment

Long-term carvedilol therapy does not affect renal perfusion autoregulation or glomerular filtration.

In hypertensive patients with renal insufficiency, no significant changes in elimination half-life or plasma Cmax have been observed. In patients with impaired renal function, the area under the plasma concentration-time curve (AUC) increases by 40–50%, and renal excretion of the parent compound is reduced. However, changes in pharmacokinetic parameters are considered minor.

Several open-label studies have shown that carvedilol is effective in patients with renal hypertension, chronic renal failure, dialysis patients, and kidney transplant recipients. After oral administration of 10 mg carvedilol, Cmax in plasma is achieved within 1–5 hours, both on dialysis and non-dialysis days. The drug is undetectable in plasma after 24 hours.

Carvedilol induces a gradual reduction in arterial blood pressure both on dialysis and non-dialysis days. The antihypertensive effect is comparable to that observed in patients with normal renal function. Carvedilol is not removed by dialysis, likely due to its high plasma protein binding, which prevents passage through the dialysis membrane.

Data from a comparative study in hemodialysis patients indicate that carvedilol is superior to diltiazem in efficacy for silent ischemia.

Patients with Hepatic Impairment

A pharmacokinetic study in patients with liver cirrhosis demonstrated that the AUC of carvedilol is 6.8 times higher than in healthy volunteers.

Therefore, carvedilol is contraindicated in patients with clinically evident hepatic impairment (see also sections "Contraindications" and "Dosage and Administration" ("Special Dose Adjustment Instructions")).

Patients with Heart Failure

A study in 24 Japanese patients with heart failure showed that the clearance of both R- and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results indicate that heart failure substantially affects the pharmacokinetics of R- and S-carvedilol.

Elderly Patients

The pharmacokinetics of Carvedilol Sandoz® are age-dependent. Plasma concentrations of carvedilol in elderly patients are 50% higher than in younger patients. In elderly individuals, Cmax and AUC may increase. Dose adjustment may be necessary in such cases.

Age did not significantly affect the pharmacokinetics of carvedilol in hypertensive patients. In a study of elderly hypertensive patients, no differences in adverse reaction profiles were observed compared to younger patients. Another study in elderly patients with ischemic heart disease revealed no differences in adverse event reporting compared to younger patients. Therefore, elderly patients do not require adjustment of the initial dose.

Pediatric Patients

Studies in children and adolescents have shown that body weight-adjusted clearance in pediatric patients is significantly higher than in adults.

Clinical characteristics.

Indications.

Mild to moderate essential hypertension.

Prevention of cardiac events in chronic angina pectoris.

Treatment of mild to severe stable heart failure (NYHA class II–IV) of ischemic or cardiomyopathic origin, as part of combination therapy with standard treatment (diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Decompensated chronic heart failure (NYHA class II–IV) in patients requiring intravenous inotropic support.
• Chronic obstructive pulmonary disease.
• Bronchial asthma (two fatal cases following status asthmaticus have been reported after a single dose).
• Allergic rhinitis.
• Laryngeal edema.
• Cor pulmonale.
• Sinus node dysfunction (including sinoatrial block).
• Severe arterial hypotension (systolic blood pressure < 85 mmHg).
• Second- and third-degree atrioventricular block (AV block).
• Severe bradycardia (resting heart rate less than 45–50 beats per minute).
• Cardiogenic shock.
• Myocardial infarction with complications.
• Hepatic dysfunction with clinical manifestations.
• Metabolic acidosis.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) (except MAO-B inhibitors).
• Slow metabolism of debrisoquin and mephenytoin.
• Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions

Effect of carvedilol on the pharmacokinetics of other medicinal products

Carvedilol is both a substrate and an inhibitor of P-glycoprotein. Therefore, when carvedilol is used concomitantly, the bioavailability of medicinal products transported by P-glycoprotein may increase. In addition, the bioavailability of carvedilol may be altered by inducers or inhibitors of P-glycoprotein.

Digoxin. In some studies in healthy volunteers and patients with heart failure, digoxin exposure increased by approximately 20%. A more pronounced effect was observed in male patients compared to female patients. Therefore, careful and strict monitoring of plasma digoxin concentration is recommended when initiating or discontinuing carvedilol therapy, as well as when reducing the dose (see section "Special precautions"). Carvedilol did not affect intravenous digoxin administration.

Cyclosporine. Two studies in kidney and heart transplant patients receiving oral cyclosporine showed increased plasma cyclosporine concentrations after initiation of carvedilol therapy. Carvedilol clearly increases oral cyclosporine exposure by approximately 10–20%. To maintain a therapeutic cyclosporine level, a reduction in cyclosporine dose by an average of 10–20% is necessary. The mechanism of this interaction is not known but may involve inhibition of intestinal P-glycoprotein. Due to high inter-individual variability, careful monitoring of plasma cyclosporine concentration is recommended after initiation of carvedilol therapy, with appropriate adjustment of cyclosporine dosage.

Effect of other medicinal products on the pharmacokinetics of carvedilol

Inhibitors and inducers of CYP2D6, CYP1A2, and CYP2C9 may stereoselectively alter systemic and/or pre-systemic metabolism of carvedilol, leading to increased or decreased plasma concentrations of R- and S-carvedilol (see sections "Pharmacokinetics" and "Metabolism"). Several examples observed in patients and healthy volunteers are listed below. The list is not exhaustive.

Rifampicin. In a study involving 12 healthy volunteers, concomitant administration of rifampicin reduced carvedilol exposure by nearly 60%. A reduction in the effect of carvedilol on systolic blood pressure was observed. The mechanism of this interaction is not known but may involve induction of intestinal P-glycoprotein by rifampicin. In patients receiving carvedilol concomitantly with rifampicin, careful monitoring of beta-blocking activity is required.

Amiodarone. In patients with heart failure receiving both carvedilol and amiodarone, the trough concentrations of R- and S-carvedilol were reduced by a factor of 2.2 compared to patients receiving carvedilol as monotherapy. The effect on S-carvedilol is attributed to desethylamiodarone, a metabolite of amiodarone, which is a potent inhibitor of CYP2C9. In vitro studies using human liver microsomes have shown that both amiodarone and desethylamiodarone inhibit the oxidation of R- and S-carvedilol. In patients receiving combination therapy with carvedilol and amiodarone, monitoring of beta-blocking activity is recommended.

Fluoxetine and paroxetine. In a randomized crossover study in 10 patients with heart failure, concomitant administration of fluoxetine, a potent CYP2D6 inhibitor, resulted in stereoselective inhibition of carvedilol metabolism, with a 77% increase in the mean AUC_0–12 of the R(+) enantiomer and a statistically significant 35% increase in the AUC of the S(–) enantiomer compared to placebo. However, no differences in adverse reactions, blood pressure, or heart rate were observed between treatment groups. The effect of a single dose of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics of oral carvedilol was studied in 12 healthy volunteers after a single oral dose. Despite significant increases in R- and S-carvedilol exposure, no clinical effects were observed in these healthy volunteers.

Pharmacodynamic interactions

Insulin and oral hypoglycemic agents. The effects of insulin and oral hypoglycemic agents may be enhanced. Symptoms of hypoglycemia may be masked or attenuated (especially tachycardia). Patients with diabetes should have regular blood glucose monitoring (see section "Special precautions").

Digoxin. Combined use of beta-blockers and digoxin may lead to additive prolongation of atrioventricular (AV) conduction time.

Verapamil, diltiazem, amiodarone, and other antiarrhythmic agents. As with other beta-blockers, oral calcium channel blockers of the verapamil and diltiazem type, amiodarone, and other antiarrhythmic agents should be used with caution, as the risk of AV conduction disturbances may increase with concomitant use. Intravenous administration of calcium channel blockers and antiarrhythmic agents should not be given during treatment with Carvedilol Sandoz®.

Drugs that reduce catecholamine levels. Patients receiving both beta-blocking agents and drugs that reduce catecholamine levels (e.g., reserpine and MAO inhibitors) should be closely monitored for signs of hypotension and/or severe bradycardia.

Antihypertensive drugs. As with other beta-blockers, Carvedilol Sandoz® may potentiate the effects or adverse reactions of other antihypertensive drugs.

Nifedipine. Concomitant use of nifedipine and Carvedilol Sandoz® may result in severe hypotension.

Clonidine. Concomitant use of clonidine with beta-blocking agents may potentiate the effects on lowering blood pressure and heart rate. When discontinuation of concomitant therapy with beta-blockers and clonidine is necessary, beta-blocker therapy should be discontinued first. Clonidine dosage may be reduced several days after stopping Carvedilol Sandoz®.

Concomitant use of Carvedilol Sandoz® and cardiac glycosides may prolong AV conduction time: inhibitors of oxidative metabolism (e.g., cimetidine) increase the plasma level of Carvedilol Sandoz® (AUC of carvedilol increased by 30%).

Anesthetics. Due to synergistic negative inotropic and hypotensive effects of Carvedilol Sandoz® and anesthetics during anesthesia, careful monitoring of vital signs is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs). Concomitant use of NSAIDs may increase blood pressure and interfere with blood pressure control.

Beta-agonist bronchodilators. Non-cardioselective beta-blockers antagonize the effects of beta-agonist bronchodilators. Close monitoring of patients is recommended.

Anesthesia and major surgery

If continued use of Carvedilol Sandoz® is required during the perioperative period, anesthetics that depress myocardial function (e.g., ether, cyclopropane, and trichloroethylene) should be used with particular caution. For information on the treatment of bradycardia and arterial hypotension, see section "Overdose".

Special precautions for use.

The drug should be used with particular caution in the following conditions:

• Pediatric age.
• Labile or secondary hypertension.
• Unstable angina.
• Complete bundle branch block of the His bundle.
• Terminal stage of peripheral arterial perfusion (e.g., Raynaud's syndrome), as beta-blockers may cause the onset or exacerbation of symptoms of arterial insufficiency.
• Recent myocardial infarction.
• Tendency to decreased arterial pressure upon change in posture (orthostasis).
• Patients concurrently receiving certain antihypertensive agents (α1-receptor blockers).

Hypersensitivity

When using beta-blockers, there is a risk of increased sensitivity to allergens and a higher frequency of serious hypersensitivity reactions (e.g., cardiovascular dysregulation, bronchospasm, dyspnea, shock) in patients with a history of severe hypersensitivity reactions and in patients undergoing desensitization therapy. Therefore, the drug should be used cautiously in such cases.

Severe cutaneous adverse reactions (SCAR)

Very rare cases of severe skin adverse reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported during carvidilol treatment (see section "Adverse reactions"). Carvedilol should not be used in patients who have experienced severe skin reactions that may be related to carvedilol.

Psoriasis

Beta-blockers, including the medicinal product Carvedilol Sandoz®, should be prescribed to patients with a history of psoriasis only after careful assessment of the benefit-risk ratio.

Withdrawal syndrome

In patients with arterial hypertension and concomitant ischemic heart disease who require discontinuation of Carvedilol Sandoz®, the dose should be gradually reduced, as is the case with all other beta-blockers.

Bradycardia

In clinical trials, bradycardia was observed in 2% of patients with arterial hypertension and in 9% of patients with heart failure. If the heart rate drops below 55 beats/min, the dose should be reduced. Arterial hypotension was reported in 9.7% and loss of consciousness in 3.4% of patients with heart failure, compared to 3.6% and 2.5% respectively in patients receiving placebo. The risk of such effects was highest during the first 30 days of treatment. This period corresponds to the titration phase (see section "Dosage and administration").

In elderly patients, high blood pressure may decrease after the first dose of Carvedilol Sandoz®.

Hyperthyroidism

Due to its beta-blocking activity, carvedilol may mask symptoms of hyperthyroidism such as tachycardia. Sudden withdrawal of the drug may lead to exacerbation of hyperthyroidism and development of a hyperthyroid crisis.

Diabetes mellitus

Particular careful monitoring is necessary for patients with diabetes mellitus, as the use of Carvedilol Sandoz® may affect blood glucose levels. Patients with diabetes should be informed that Carvedilol Sandoz® may increase insulin resistance and may mask or diminish symptoms of hypoglycemia, especially tachycardia. Non-selective beta-blockers may exacerbate insulin-induced hypoglycemia and delay normalization of serum glucose levels. Blood glucose levels should be monitored regularly, and doses of insulin or oral antidiabetic agents should be adjusted if necessary.

In patients with heart failure and concomitant diabetes mellitus, the use of Carvedilol Sandoz® may lead to worsening hyperglycemia, requiring intensification of hypoglycemic therapy. Close monitoring of blood glucose levels is recommended during treatment with Carvedilol Sandoz®; doses should be adjusted or, if necessary, treatment discontinued.

In patients with arterial hypertension and concomitant diabetes mellitus not requiring insulin, carvedilol did not affect fasting and postprandial blood glucose levels or glycated hemoglobin A1. No adjustment of antidiabetic drug dosage was required.

In insulin-independent diabetic patients, carvedilol did not have a statistically significant effect on glucose tolerance test results. In patients with arterial hypertension without diabetes but with impaired insulin response (metabolic syndrome), carvedilol slightly improved insulin sensitivity. The same was observed in patients with arterial hypertension and non-insulin-dependent diabetes.

Contact lenses

Patients using contact lenses should be informed about the possible reduction in tear production.

Heart failure

During the titration phase of Carvedilol Sandoz® in patients with heart failure, worsening of heart failure symptoms and edema have been observed. If such symptoms occur, diuretic dosage should be increased, while the dose of Carvedilol Sandoz® should remain unchanged until the patient's condition stabilizes. Temporary reduction of the dose of Carvedilol Sandoz® or discontinuation of treatment may be necessary (see section "Dosage and administration").

Carvedilol Sandoz® should be prescribed cautiously to patients with decompensated heart failure already receiving digitalis (e.g., digoxin), diuretics, and/or ACE inhibitors, as digitalis and Carvedilol Sandoz® may both slow AV conduction, and Carvedilol Sandoz® may increase digitalis levels (see also section "Interaction with other medicinal products and other forms of interaction").

Renal function in heart failure

During treatment with carvedilol in patients with decompensated heart failure and low blood pressure (systolic blood pressure < 100 mmHg), ischemic heart disease or other vascular disorders and/or renal impairment, reversible worsening of renal function has been observed. After discontinuation of the drug, renal function parameters returned to baseline levels. Renal function should be monitored during the titration phase in patients with heart failure who have risk factors. If worsening occurs, the dose should be reduced or treatment discontinued.

Pheochromocytoma

Carvedilol Sandoz® should be prescribed to patients with pheochromocytoma only if adequate α-receptor blockade is ensured. Although Carvedilol Sandoz® combines both pharmacological properties, there is currently no sufficient experience. Therefore, Carvedilol Sandoz® should be used cautiously in patients with pheochromocytoma.

Prinzmetal's angina

Drugs with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's angina. Clinical experience with carvedilol in such patients is lacking, although the alpha-blocking activity of carvedilol may prevent the development of such symptoms. However, Carvedilol Sandoz® should be used cautiously in patients suspected of having Prinzmetal's angina.

Chronic obstructive pulmonary disease

Beta-blockers may exacerbate bronchial obstruction; therefore, these drugs are not recommended for patients with chronic lung disease. Carvedilol Sandoz® may be cautiously prescribed to patients with mild lung disease if other treatments are ineffective. The lowest effective dose should be used to minimize inhibition of endogenous and exogenous β-agonists. Increased airway resistance may lead to breathing difficulties.

Patients with chronic obstructive pulmonary disease were included in clinical trials only if they did not require oral or inhaled medications for treatment of this condition. The recommended dose must be strictly followed and reduced if bronchospasm is suspected during the titration phase (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic function

Mild liver cell injury has occasionally been observed during treatment with carvedilol. In controlled trials in patients with arterial hypertension, the incidence of liver function disorder, recorded as an adverse reaction, was 1.1% (13 out of 1142 individuals) in patients receiving carvedilol and 0.9% (4 out of 462 individuals) in patients receiving placebo. One patient receiving carvedilol was withdrawn from a placebo-controlled study due to liver dysfunction.

In controlled trials in patients with chronic heart failure, the incidence of liver function disorder, recorded as an adverse effect, was 5.0% (38 out of 765 individuals) in patients receiving carvedilol and 4.6% (20 out of 437 individuals) in patients receiving placebo.

Three patients treated with carvedilol (0.4%) and two patients treated with placebo (0.5%) were withdrawn from placebo-controlled studies due to liver dysfunction.

Liver injury has been shown to be reversible and occurs with minor clinical symptoms after short- and long-term therapy. No fatal outcomes due to liver dysfunction have been reported. Laboratory tests should be performed if the first symptoms/signs of liver dysfunction appear (e.g., pruritus, dark urine, persistent anorexia, jaundice, pain on palpation in the right upper quadrant, or unexplained flu-like symptoms). If laboratory results confirm liver injury or jaundice, carvedilol should be discontinued and not restarted.

Patients should be given the following instructions:

• Do not interrupt or discontinue Carvedilol Sandoz® without consulting a physician;
• Patients with heart failure should contact their physician if they notice signs or symptoms of worsening heart failure (weight gain or dyspnea);
• Patients may experience low blood pressure while standing, which may lead to dizziness and, in some cases, loss of consciousness; such patients should sit or lie down if these symptoms occur;
• Patients experiencing fatigue and dizziness should not drive or operate complex machinery; this also applies to all patients at the beginning of treatment and during the dose titration period;
• Patients should contact their physician if they experience dizziness or loss of consciousness during the titration phase;
• Carvedilol Sandoz® should be taken with food;
• Diabetic patients should inform their physician of any changes in blood glucose levels;
• Patients using contact lenses should be informed about the possible reduction in tear production.

Use during pregnancy or breastfeeding.

Clinical experience with the use of carvedilol in pregnant women is limited. Animal studies show reproductive toxicity. The potential risk in humans is unknown.

Unless absolutely necessary, carvedilol should not be used during pregnancy.

Beta-blockers reduce placental perfusion, which may lead to intrauterine fetal death, miscarriage, or premature delivery. In addition, adverse effects may occur in the fetus and newborn (especially hypoglycemia and bradycardia). Newborns may be at increased risk of cardiac and pulmonary complications in the postnatal period. Animal studies have not provided evidence of teratogenicity of carvedilol.

Carvedilol is contraindicated during breastfeeding. Breastfeeding should be discontinued during treatment with carvedilol. Animal studies have demonstrated that carvedilol and/or its metabolites are excreted in rat milk. It is unknown whether carvedilol is excreted in human breast milk. Most beta-blockers, especially lipophilic substances, are excreted in human milk in varying amounts.

Beta-blocker therapy should be discontinued 72–48 hours before the expected delivery date. If this is not possible, newborns should be closely monitored during the first 48–72 hours of life.

Ability to affect reaction speed when driving or operating machinery.

Such studies have not been conducted. Due to possible adverse reactions (e.g., dizziness, fatigue) during the use of Carvedilol Sandoz®, patients should refrain from driving and operating potentially hazardous machinery. Particular attention should be paid at the beginning of treatment, after dose increases, when using other medicinal products, or when combined with alcohol.

Method of Administration and Dosage

Essential Hypertension

Adults

The initial dose is 12.5 mg once daily for the first two days. Thereafter, treatment with a dose of 25 mg once daily is recommended. If the effect is insufficient, the daily dose may be gradually increased up to 50 mg in one or two divided doses (with intervals of at least 2 weeks). The maximum dose in arterial hypertension is 50 mg.

Elderly Patients

Initial dose: 12.5 mg once daily. For some patients, this dose is sufficient for adequate blood pressure control. If the effect is insufficient, the daily dose may be gradually increased up to a maximum of 50 mg in one or two divided doses.

Angina Pectoris

The initial dose is 12.5 mg twice daily for the first two days. Thereafter, treatment with a dose of 25 mg twice daily is recommended. If the effect is insufficient, the daily dose may be gradually increased up to a maximum of 100 mg in two divided doses (with intervals of at least 2 weeks).

Elderly Patients

The dose should generally not exceed 25 mg twice daily.

Treatment of Mild to Severe Heart Failure (NYHA Class II–IV)

Dosage should be individually titrated with careful monitoring of the patient during the titration phase.

The doses of digitalis, diuretics, and ACE inhibitors should be stabilized prior to initiating treatment with Carvedilol Sandoz®.

The recommended starting dose is 3.125 mg twice daily for two weeks. If this dose is well tolerated, it may be gradually increased (with intervals of at least 2 weeks) to 6.25 mg twice daily, then to 12.5 mg twice daily (twice daily, one tablet of Carvedilol Sandoz® 12.5 mg), and finally to 25 mg twice daily (twice daily, one tablet of Carvedilol Sandoz® 25 mg). The dose should be titrated to the highest dose that is well tolerated by the patient.

The maximum recommended dose is 25 mg twice daily for patients with body weight ≤85 kg and 50 mg twice daily for patients with body weight >85 kg.

Before increasing the dose, the physician should examine the patient for signs of worsening heart failure, vasodilation (hypotension, dizziness), or bradycardia. Transient worsening of heart failure or edema should be managed by concomitant use of increased diuretic doses. However, dose reduction of Carvedilol Sandoz® or temporary discontinuation of treatment may be required.

If Carvedilol Sandoz® has been discontinued for more than two weeks, therapy should be resumed at a dose of 3.125 mg twice daily, with gradual dose escalation (at intervals of at least 2 weeks), as described above. Initial symptoms of vasodilation should be managed by reducing the diuretic dose. If symptoms persist, the dose of ACE inhibitors should be reduced, followed by dose reduction of Carvedilol Sandoz®. Under such circumstances, the dose of this medicinal product should not be increased until symptoms of worsening heart failure and vasodilation have resolved.

Special Dosing Instructions

Patients with Chronic Heart Failure and Renal Impairment

The required dose should be individually determined for each patient. According to the pharmacokinetic data of Carvedilol Sandoz®, patients with heart failure and moderate to severe renal impairment do not require dose adjustment of Carvedilol Sandoz® (see section "Pharmacokinetics").

Patients with Hepatic Impairment

Carvedilol Sandoz® is contraindicated in patients with clinical signs of hepatic impairment (see also sections "Pharmacokinetics" and "Contraindications").

Method of Administration

Tablets should be swallowed with sufficient fluid.

The tablets do not necessarily need to be taken with food. However, patients with heart failure should take the tablets with food to slow absorption and reduce the frequency of orthostatic effects. Treatment with Carvedilol Sandoz® is generally long-term. As with other β-blockers, discontinuation of carvedilol should not be abrupt but should be achieved by gradually reducing the dose over several days (e.g., halving the dose every 3 days). This is particularly important for patients with concomitant ischemic heart disease.

Children

The safety and efficacy of Carvedilol Sandoz® in patients under 18 years of age have not been established; therefore, the use of this medicinal product in children is not recommended.

Overdose

Symptoms

Overdose may cause severe arterial hypotension, bradycardia, heart failure, cardiogenic shock, and cardiac arrest. In addition, respiratory depression, bronchospasm, vomiting, impaired consciousness, and generalized seizures may occur.

Treatment

In addition to standard supportive measures, vital signs should be monitored and corrected as necessary in an intensive care setting. In certain cases, mechanical ventilation may be required.

Absorption of carvedilol in the gastrointestinal tract may be reduced by gastric lavage, administration of activated charcoal, and laxatives.

The patient should be placed in a supine position.

The following medicinal products may be used as antidotes:

For bradycardia

Atropine: 0.5–2 mg intravenously; bradycardia refractory to treatment may require the use of a cardiac pacemaker.

For arterial hypotension and shock

Plasma expanders and sympathomimetics, if necessary.

The beta-blocking effect of Carvedilol Sandoz® may be attenuated and reversed by slow intravenous administration of sympathomimetics in varying doses depending on body weight, such as isoprenaline, dobutamine, orciprenaline, or adrenaline. This effect is dose-dependent. If positive inotropic agents are required, phosphodiesterase inhibitors such as milrinone should be administered. Glucagon (1 to 10 mg intravenously) may be administered, followed by continuous infusion at 2 to 5 mg/hour, if necessary.

If peripheral vasodilation is the predominant reaction of intoxication, noradrenaline or norepinephrine may be required under continuous cardiovascular monitoring.

In case of bronchospasm, β-sympathomimetics (by inhalation or intravenous administration if insufficient effect) or intravenous aminophylline as a slow injection or infusion should be used. For seizures, diazepam or clonazepam should be administered slowly intravenously.

Carvedilol cannot be removed by dialysis, as the active substance is not dialyzable, likely due to its high degree of plasma protein binding.

Important Note

Since in cases of severe overdose with shock symptoms, the elimination half-life of the drug from tissue depots may be prolonged, supportive therapy should be continued for a sufficiently long period. The duration of supportive detoxification therapy depends on the severity of the overdose and should be continued until the patient's condition stabilizes.

Adverse Reactions

The frequency of adverse reactions is dose-independent, except for dizziness, visual disturbances, and bradycardia.

Frequency of adverse reactions is categorized as follows:

Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1000 to < 1/100); Rare (≥ 1/10,000 to < 1/1000); Very rare (< 1/10,000).

Blood and lymphatic system disorders

Common: Anaemia.

Rare: Thrombocytopenia.

Very rare: Leukopenia.

Cardiac disorders

Very common: Heart failure.

Common: Bradycardia, oedema, hypervolaemia, fluid retention.

Uncommon: Atrioventricular block, angina pectoris.

Eye disorders

Common: Visual disturbance, decreased lacrimation (dry eyes), eye irritation.

Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain.

Uncommon: Constipation.

Rare: Dry mouth.

General disorders

Very common: Asthenia (fatigue).

Common: Oedema, pain.

Hepatobiliary disorders

Very rare: Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT).

Immune system disorders

Very rare: Hypersensitivity (allergic reactions).

Infections and infestations

Common: Pneumonia, bronchitis, upper respiratory tract infections, urinary tract infections.

Metabolism and nutrition disorders

Common: Weight gain, hypercholesterolaemia, impaired glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes.

Musculoskeletal and connective tissue disorders

Common: Limb pain.

Nervous system disorders

Very common: Dizziness, headache.

Common: Syncope, pre-syncope.

Uncommon: Paraesthesia.

Psychiatric disorders

Common: Depression, depressed mood.

Uncommon: Sleep disorders, nightmares, hallucinations, loss of consciousness.

Very rare: Psychosis.

Renal and urinary disorders

Common: Worsening of renal function and renal failure in patients with diffuse vascular disease and/or pre-existing renal insufficiency.

Rare: Urinary dysfunction.

Very rare: Urinary incontinence in women.

Reproductive system and breast disorders

Uncommon: Erectile dysfunction.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients.

Rare: Nasal congestion.

Skin and subcutaneous tissue disorders

Uncommon: Skin reactions (e.g., allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichenoid skin lesions).

Very rare: Severe skin reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Vascular disorders

Very common: Arterial hypotension.

Common: Orthostatic hypotension, disturbances in peripheral circulation (cold extremities, peripheral vascular disease, worsening of intermittent claudication, and Raynaud's syndrome), arterial hypertension.

Description of selected adverse reactions

Dizziness, syncope, headache, and asthenia are usually mild and occur more frequently at the beginning of treatment.

In patients with congestive heart failure, worsening of heart failure and fluid retention may occur during dose escalation of carvedilol (see section "Warnings and Precautions").

Heart failure was a commonly reported adverse event in patients receiving placebo and carvedilol (14.5% and 15.4%, respectively) in patients with left ventricular dysfunction following acute myocardial infarction.

Reversible worsening of renal function has been observed during carvedilol therapy in patients with chronic heart failure, low blood pressure, ischaemic heart disease, and/or underlying renal impairment (see section "Warnings and Precautions").

In addition, the following have been observed:

• Increased symptoms in patients with intermittent claudication or Raynaud's syndrome,
• Worsening of diagnosed heart failure in isolated cases,
• Mild liver injury (rare cases) (see section "Special Warnings and Precautions for Use"),
• Skin lesions resembling lichen planus,
• Initiation or exacerbation of psoriasis,
• Due to possible increased airway resistance in patients predisposed to bronchospastic reactions, breathing difficulties or asthma attacks may occur (see section "Special Warnings and Precautions for Use").

Post-marketing experience

During the post-marketing period, the following adverse reactions have been reported with carvedilol. Since these reports come from an undefined population, it is not always possible to reliably estimate their frequency and/or establish a causal relationship to drug exposure.

Metabolism and nutrition disorders

Due to its β-blocking properties, the drug may precipitate latent diabetes, worsen manifestations of existing diabetes, and impair glucose control (see section "Warnings and Precautions"). Impaired glucose regulation (hypoglycaemia) has been observed.

Skin and subcutaneous tissue disorders

Alopecia. Severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders

In rare cases, urinary incontinence in women has been reported. The symptom resolves after discontinuation of the drug.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep the blister in the original carton to protect from light. Store out of reach and sight of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

SALUTAS Pharma GmbH.

Manufacturer's address and place of business.

Otto-von-Guericke-Allee 1, 39179 Barleben, Saxony-Anhalt, Germany.